This project investigates the expression of proto-oncogenes and other cell cycle regulatory genes in the embryonic chicken lens to determine their relationship to cell growth, quiescence, and differentiation. The normal developmental profiles of six nuclear proto-oncogene messenger ribonucleic acid (mRNAs) (c-myc, N-myc, c-fos, c-jun, Rb, and p53) and the cell cycle regulatory protein, cyclin B, have been completed. The unexpected finding that cyclin B is present in postmitotic lens fiber cells and that it is complexed with p34cdc2 suggests that lens fiber cell differentiation may involve aberrant progression through the cell cycle. To test this hypothesis, a line of transgenic mice has been produced that overexpresses Wee1 (a protein kinase that inhibits cyclin B/p34cdc2) under control of the ~-crystallin promoter to target expression to postmitotic lens fiber cells. Preliminary analysis of lenses from this transgenic line indicates that len fiber denucleation may be abnormal. Similarities between apoptosis and lens fiber differentiation prompted us to compare proto-oncogene expression in differentiating and apoptotic cells. The earliest difference we have detec d between these two processes is deregulation of c-fos, c-jun, and c-myc expression during apoptosis. We have demonstrated that expression of these proto-oncogenes is strictly regulated by 12(S)HETE synthesis and are exploring the mechanism of this effect through analysis of the c-fos promoter. Candidate genes that may be regulated by these proto-oncogenes are being explored through transfection of cultured cells and deoxyribonucleic acid (DNA) binding studies. We have demonstrated that cyclin B is expressed during apoptosis of postmitotic PC12 cells, where it complexes with p34cdc2 and with a novel, 40K member of the PCTAIRE family. The identity and function of this 40K protein are being investigated.[unreadable]GRANT 01EY00251 We generated transgenic mice and rats expressing interferon (IFN)-gamma in their lenses to investigate the possible role of this lymphokine in ocul pathogenesis. Embryonic lens and retina differentiation were affected in t alphaA-crystallin/IFN-gamma transgenic mice resulting in microphthalmia, microphakia, retinal detachment, and persistent hyperplastic primary vitreous in the adult mice. Major histocompatibility complex (MHC) class I messenger ribonucleic acid (mRNA) levels were significantly increased in th transgenic eyes, and MHC class II proteins were expressed in their cornea, iris, ciliary body, choroid, lens, and retinal pigment epithelial (RPE). Constitutive expression of IFN-gamma and its induction of MHC class II molecules in the eye provide a useful model to study the linkage between aberrant MHC class II expression and predisposition to autoimmunity and the role of IFN-gamma in the treatment of inflammatory eye diseases and cytokine signaling during embryonic eye development. Fibroblast growth factor (FGF)-3 expression was directed to the eye to investigate how the aberrant expression of this growth factor would affect the developmental program of the eye. The alphaA-crystallin/FGF-3 transgenic mice presented exophthalmic and aberrant elongation of central lens epithelia at 15 days of embryonic development. The hypertrophic lens mass was extruded through the cornea at 16 days of embryonic development, resulting in cornea perforation. Postnatal microphthalmia was characterize by intraocular hyperplastic glandular structures replacing the normal iris, ciliary body, and lens.